17th International Mass Spectrometry Conference :: Prague, 2006
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|Session:||Drug Discovery and Development|
|Presentation date:||Tue, Aug 29, 2006|
|Presentation time:||14:30 – 16:00|
Sam Wainhaus1, Cymbelene Nardo1, Kimberly Dunn-Meynell1, Shiyong Wang1, Ryan Anstatt1, Walter Korfmacher11 Schering-Plough Research Institute, Kenilworth, United States
Correspondence address: Sam Wainhaus, Schering-Plough Research Institute, Exploratory Drug Metabolism, 2015 Galloping Hill Road, K15-2-2945, Kenilworth, NJ, 07033 United States.
Keywords: Mass Spectrometry, Liquid Chromatography; Pharmaceutical; Pharmacokinetics; Quadrupole, Triple.
Novel aspect: The application of UPLC and automated method development (UPLC-MS/MS) to rapid pharmacokinetic screening in drug discovery.
There is an increasing demand, within the pharmaceutical industry, for higher throughput pharmacokinetic and metabolic screening. The rationale behind this undertaking lies in the advancement of lead compounds that have the highest probability for success. We have approached this task from a drug metabolism/pharmacokinetics perspective with Liquid Chromatography-Mass Spectrometry/Mass Spectrometry (LC-MS/MS) as our principal tool in an effort to satisfy these demands.
We have implemented a novel pharmacokinetic paradigm called Cassette Accelerated Rapid Rat Screening (CARRS) and a similar assay for monkeys and dogs. This rugged assay comprises the use of fast LC-MS/MS and highly organized interdepartmental collaboration between chemistry, animal dosing facility and drug metabolism to screen 42 new compounds per week. In order to achieve rapid turnaround time, high quality and informative data we have utilized a variety of approaches that will be discussed in this paper.
Our initial approach utilized ballistic gradient HPLC-MS/MS using a Shimadzu HPLC and TSQ Quantum. Our most recent approach utilizes ultra performance liquid chromatography (UPLC)-tandem mass spectrometry. UPLC provides improved chromatographic separation and sensitivity while dimishing carryover. We have used the Waters Acquity UPLC in conjunction with both the Micromass Premier and TSQ Quantum triple quadrupole mass spectrometers. We have developed a generic approach to rapidly provide pharmacokinetic information by using automated method development software such as QuanOptimize and QuickQuan. This EZ-CARRS approach has facilitated significantly improved turnaround time including same day reporting of data. Additionally, we have introduced a metabolic profiling assay (in plasma) that is connected to the CARRS assay, allowing for the routine profiling of both common and unique metabolites including estimated AUCís without an authentic standard.
These approaches have had a major impact within drug discovery in giving program teams the ability to make decisions on the fly regarding specific compounds as well as a series of analogs.